Cell migration is a major driving force in embryonic development, wound healing, and tumor metastasis. Therefore, understanding the molecular mechanisms that control cell motility is significant for human health. My laboratory has developed a relatively simple and genetically tractable model for the study of cell migration, the movement of a small group of cells in the Drosophila ovary known as the border cells. In the previous funding period we have identified and characterized a number of new border cell migration genes. We also overcame a major technical obstacle and succeeded in time-lapse, live-imaging of migrating border cells. We propose to build upon these advances to address a major unsolved question in the field of cell migration: how cell polarity and cytoskeletal dynamics are integrated to achieve coordinated, directed migration of a group of cells. To address this general question, we will combine genetic approaches, live-imaging and biochemistry with two specific aims. The first is to test the hypothesis that a protein we have named FAV, and its mammalian homologs, amplify EGFR-dependent cell polarity and integrate EGFR signaling, trafficking and cell polarity with actin dynamics. The second aim is to test the hypothesis that a newly identified protein, Tiarin, and its human homolog, are conserved regulators of actin dynamics and cell motility. Together these studies will provide insights into the mechanisms controlling border cell migration, correlate the findings with the broader field of actin dynamics, and use this model to identify and characterize genes important in human health and disease. PUBLIC HEALTH RELEVANCE: The ability to move is a property of cells from virtually all animals, from simple ones such as flies and worms, all the way to humans. The proposed research focuses on the movement of a small group of cells in the fruitfly, to learn more about how specific molecules orchestrate when, where and how they move. Since cell motility contributes to wound healing and tumor metastasis, these studies could lead to the discovery of new drug targets that could promote healing or inhibit the spread of cancer cells.